U.S. patent number 8,809,343 [Application Number 13/142,076] was granted by the patent office on 2014-08-19 for pyrimidine derivative, preparation method and use thereof.
This patent grant is currently assigned to Fudan University. The grantee listed for this patent is Fener Chen, Yonghong Liang, Zhaosen Zeng. Invention is credited to Fener Chen, Yonghong Liang, Zhaosen Zeng.
United States Patent |
8,809,343 |
Chen , et al. |
August 19, 2014 |
Pyrimidine derivative, preparation method and use thereof
Abstract
A pyrimidine derivative and the preparation method and use
thereof. The said pyrimidine derivative is a diaryl pyrimidine
derivative or a diaryl benzo pyrimidine derivative which has the
structure shown as the Formula I and IV. ##STR00001## Present
pyrimidine derivative can be used for the prevention or the
treatment of HIV.
Inventors: |
Chen; Fener (Shanghai,
CN), Liang; Yonghong (Shanghai, CN), Zeng;
Zhaosen (Shanghai, CN) |
Applicant: |
Name |
City |
State |
Country |
Type |
Chen; Fener
Liang; Yonghong
Zeng; Zhaosen |
Shanghai
Shanghai
Shanghai |
N/A
N/A
N/A |
CN
CN
CN |
|
|
Assignee: |
Fudan University (Shanghai,
CN)
|
Family
ID: |
42286907 |
Appl.
No.: |
13/142,076 |
Filed: |
December 24, 2009 |
PCT
Filed: |
December 24, 2009 |
PCT No.: |
PCT/CN2009/075931 |
371(c)(1),(2),(4) Date: |
September 12, 2011 |
PCT
Pub. No.: |
WO2010/072155 |
PCT
Pub. Date: |
July 01, 2010 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20120122902 A1 |
May 17, 2012 |
|
Foreign Application Priority Data
|
|
|
|
|
Dec 26, 2008 [CN] |
|
|
200810208011 |
Dec 26, 2008 [CN] |
|
|
200810208012 |
Jun 18, 2009 [CN] |
|
|
200910053345 |
|
Current U.S.
Class: |
514/258.1;
544/316 |
Current CPC
Class: |
C07D
239/50 (20130101); C07D 239/93 (20130101); A61P
37/00 (20180101); C07D 239/94 (20130101); C07D
239/47 (20130101); C07D 239/95 (20130101); C07D
239/48 (20130101); C07D 239/88 (20130101); C07D
239/84 (20130101); C07D 401/12 (20130101); A61P
31/18 (20180101) |
Current International
Class: |
A01N
43/54 (20060101); C07D 239/02 (20060101); A61K
31/517 (20060101) |
Field of
Search: |
;544/316 ;514/258.1 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
1486310 |
|
Mar 2004 |
|
CN |
|
1697830 |
|
Nov 2005 |
|
CN |
|
101031551 |
|
Sep 2007 |
|
CN |
|
101121698 |
|
Feb 2008 |
|
CN |
|
101282945 |
|
Oct 2008 |
|
CN |
|
101463014 |
|
Jun 2009 |
|
CN |
|
101602733 |
|
Dec 2009 |
|
CN |
|
03/030909 |
|
Apr 2003 |
|
WO |
|
2006/002422 |
|
Jan 2006 |
|
WO |
|
2008/079907 |
|
Jul 2008 |
|
WO |
|
Other References
International Search Report of PCT/CN2009/075931 dated Apr. 1,
2010. cited by applicant .
Liu et al., "Discovery of a new class of 4-anilinopyrimidines as
potent c-Jun N-terminal kinase inhibitors: synthesis and SAR
studies," Bioorganic & Medicinal Chemistry Letters 17, 2007,
pp. 668-672. cited by applicant .
Liang et al.," Design, synthesis, and SAR of naphthyl-substituted
diarylpyrimidines as non-nucleoside inhibitors of HIV-1 reverse
transcriptase," ChemMedChem, 2009, vol. 4, pp. 1537-1545. cited by
applicant .
Feng et al., "Structural modifications of DAPY analogues with
potent anit-HIV-1 activity," ChemMedChem, 2009, vol. 4, pp.
219-224. cited by applicant .
Nayana et al., "Insight into the structural requirements of proton
pump inhibitors based on CoMFA and CoMSIA studies," Journal of
Molecular Graphics and Modelling, 2008, vol. 27, pp. 233-243. cited
by applicant .
CA (American Chemical Society), CAN 143:326363, 1978, vol. 143, CAS
RN=64778-44-5, 64778-48-9, 64778-69-4, 64778-70-7, 5 pages total.
cited by applicant.
|
Primary Examiner: Ward; Paul V.
Attorney, Agent or Firm: Hamre, Schumann, Mueller &
Larson, P.C.
Claims
What is claimed is:
1. A compound or pharmaceutically acceptable salts thereof, wherein
the compound has the structure shown as the formula I: ##STR00039##
wherein -a.sup.1=a.sup.2-a.sup.3=a.sup.4- represents the structure
of a divalent free radical and is selected from:
--CH.dbd.CH--CH.dbd.CH--, --N.dbd.CH--CH.dbd.CH--,
--CH.dbd.N--CH.dbd.CH--, --N.dbd.N--CH.dbd.CH--,
--N.dbd.CH--N.dbd.CH--, --N.dbd.CH--CH.dbd.N--;
-b.sup.1=b.sup.2-b.sup.3=b.sup.4- represents the structure of a
divalent free radical and is selected from:
--CH.dbd.CH--CH.dbd.CH--, --N.dbd.CH--CH.dbd.CH--,
--N.dbd.N--CH.dbd.CH--, --N.dbd.CH--N.dbd.CH--,
--N.dbd.CH--CH.dbd.N--; R.sup.1 and R.sup.2 respectively are
separately selected from hydrogen, hydroxyl, halogen, substituted
C.sub.1-4 alkyl, substituted C.sub.2-6 alkenyl, substituted
C.sub.2-6 alkynyl, C.sub.1-6 alkoxyl, cyano-group, nitryl,
amino-group, --NH(OH)--, --N(R.sup.6)p--; R.sup.13 and R.sup.14
respectively are separately selected from hydrogen, hydroxyl,
halogen, substituted C.sub.1-4 alkyl, substituted C.sub.2-6
alkenyl, substituted C.sub.2-6 alkynyl, C.sub.1-6 alkoxyl,
cyano-group, nitryl, amino-group, --NH(OH)--, --N(R.sup.6)p--;
R.sup.3 and R.sup.4 respectively are separately selected from
hydrogen, hydroxyl, halogen, C.sub.1-6 alkyl substituted by
cyano-group or --C(.dbd.O)R.sup.6, C.sub.3-7 cycloalkyl, C.sub.2-6
alkenyl substituted by one or more halogen atoms or cyano-groups,
C.sub.2-6 alkynyl substituted by one or more halogen atoms or
cyano-groups, C.sub.1-6 alkoxycarbonyl, carboxyl, cyano-group,
nitryl, amino-group, --NR.sup.5--, methyl polyhalide, methoxyl
polyhalide, methylthio polyhalide, --S(.dbd.O).sub.pR.sup.7,
--NH--S(.dbd.O).sub.pR.sup.7, --C(.dbd.O)R.sup.7, --NHC(.dbd.O)H,
--C(.dbd.O)NHNH.sub.2, --NHC(.dbd.O)R.sup.7, and
--C(.dbd.NH)R.sup.7; R.sup.5 represents hydrogen, C.sub.1-6
alkycarbonyl, aryl, formoxyl, C.sub.1-6 alkyl, C.sub.1-6
alkoxycarbonyl; X is selected from --NR.sup.6--, --NH--NH--,
--N.dbd.N--, --O--, --C(.dbd.O)--, C.sub.1-4 alkanediyl, --CHOH--,
--S--, --S(.dbd.O)p--, -X.sub.1-C.sub.1-4 alkanediyl- or -C.sub.1-4
alkanediyl-X.sub.1-, and --CH(CN)--; X.sub.1 is selected from
--NR.sup.6--, --NH--NH--, --N.dbd.N--, --O--, --C(.dbd.O)--,
--CHOH--, and --S(.dbd.O)p--; R.sup.6 is separately selected from
hydrogen, aryl, formoxyl, C.sub.1-6 alkycarbonyl, C.sub.1-6 alkyl,
C.sub.1-6 alkoxycarbonyl, C.sub.1-6 alkyl substituted by formoxyl,
C.sub.1-6 alkycarbonyl, C.sub.1-6 alkoxycarbonyl or C.sub.1-6
alkycarboxyl, C.sub.1-6 alkoxyl and C.sub.1-6 alkoxycarbonyl
substituted by C.sub.1-6 alkoxycarbonyl; R.sup.7 is selected from
amino-group-, --NH--NH--, mono- or di-(C.sub.1-4 alkyl) amino-group
and C.sub.1-4 alkyl polyhalide, wherein where R.sup.3 is
--S(.dbd.O).sub.pR.sup.7, R.sup.7 is selected from --NH--NH-- and
C.sub.1,4 alkyl polyhalide; m is an integer from 0 to 5, n is an
integer from 0 to 6; and P is an integer of 1 or 2.
2. The compound or pharmaceutically acceptable salts thereof of
claim 1, wherein the compound has the structure shown as the
formula II: ##STR00040##
3. The compound or pharmaceutically acceptable salts thereof of
claim 1, wherein the compound has the structure shown as the
formula III: ##STR00041##
4. The compound or pharmaceutically acceptable salts thereof of
claim 1, wherein the salts are selected from hydrochloride,
sulfate, tartrate, citrate, fumarate, and malate.
5. A compound or pharmaceutically acceptable salts thereof, wherein
the compound has the structure shown as the formula IV ##STR00042##
wherein R.sup.8 is separately selected from aryl, substituted aryl,
naphthyl, substituted naphthyl, 5- or 6-membered aromatic
heterocyclic, C.sub.1-6 alkoxycarbonyl, aryloxycarbonyl, and
substituted aryloxycarbonyl; R.sup.9 and R.sup.10 respectively are
separately selected from hydrogen, hydroxyl, halogen, C.sub.1-6
alkoxyl, C.sub.1-6 alkoxycarbonyl, carboxyl, cyano-group, nitryl,
amino-group, --NR.sup.11--, methyl polyhalide, methoxyl polyhalide,
methylthio polyhalide, --S(.dbd.O).sub.pR.sup.12,
--NH--S(.dbd.O).sub.pR.sup.12, --C(.dbd.O)R.sup.12, --NHC(.dbd.O)H,
--C(.dbd.O)NHNH.sub.2, --NHC(.dbd.O)R.sup.12, and
--C(.dbd.NH)R.sup.12; Z and Y respectively are separately selected
from --NR.sup.11--, --NH--, --NH--NH--, --N.dbd.N--, --O--,
--C(.dbd.O)--, C.sub.1-4 alkanediyl, --CH(OH)--, --S--,
--S(.dbd.O)p--, -X.sub.2-C.sub.1-4 alkanediyl, -C.sub.1-4
alkanediyl-X.sub.2-, and --CH(CN)--; X.sup.2 is selected from
--NR.sup.11--, --NH--NH--, --N.dbd.N--, --O--, --C(.dbd.O)--,
--CH(OH)--, and --S(.dbd.O)p--; R.sup.11 is separately selected
from aryl, formoxyl, C.sub.1-6 alkycarbonyl, C.sub.1-6 alkyl,
C.sub.1-6 alkoxycarbonyl, C.sub.1-6 alkyl substituted by formoxyl,
C.sub.1-6 alkycarbonyl, C.sub.1-6 alkoxycarbonyl or C.sub.1-6
alkycarboxyl, C.sub.1-6 alkoxyl and C.sub.1-6 alkoxycarboxyl
substituted by C.sub.1-6 alkoxycarbonyl; R.sup.12 is selected from
C.sub.1-4 alkyl, amino-group, mono- or di-(C.sub.1-4 alkyl)
amino-group and C.sub.1-4 alkyl polyhalide; m is an integer from 0
to 5, n is an integer from 0 to 6; and P is an integer of 1 or
2.
6. The compound of claim 5, wherein the pharmaceutically acceptable
salts are selected from hydrochloride, sulfate, tartrate, citrate,
fumarate, and malate.
7. The compound of claim 1, wherein X is --O--.
8. The compound of claim 5, wherein Z is --O--.
9. The compound of claim 1, wherein R3 is the cyano-group.
10. A pharmaceutical composition, wherein the pharmaceutical
composition comprises an effective dosage of a compound or
pharmaceutically acceptable salts thereof of claim 1, and
pharmaceutically acceptable carriers.
11. A pharmaceutical composition, wherein the pharmaceutical
composition comprises an effective dosage of a compound or
pharmaceutically acceptable salts thereof of claim 5, and
pharmaceutically acceptable carriers.
12. A method of manufacturing a medicament, comprising mixing a
compound or pharmaceutically acceptable salts thereof in accordance
with claim 1 with a pharmaceutically acceptable carrier.
13. A method of manufacturing a medicament, comprising mixing a
compound or pharmaceutically acceptable salts thereof in accordance
with claim 5 with a pharmaceutically acceptable carrier.
14. A method for preparing the compound in accordance with claim 5,
comprising: (a) mixing 4-chloro benzo pyrimidine, substituted
phenol or aniline, and polar aprotic solvent to react according to
the following general equation to obtain the compound in accordance
with claim 5; ##STR00043## or, comprising: (b) heating 2-chloro
benzo pyrimidine and substituted phenol or aniline to 150.degree.
C.-210.degree. C. to fuse to react according to the following
general equation, to obtain the compound according to claim 5;
##STR00044## wherein, R.sup.8 is separately selected from aryl,
substituted aryl, naphthyl, substituted naphthyl, 5- or 6-membered
aromatic heterocyclic, C.sub.1-6 alkoxycarbonyl, aryloxycarbonyl,
and substituted aryloxycarbonyl; R.sup.9 and R.sup.10 respectively
are separately selected from hydrogen, hydroxyl, halogen, C.sub.1-6
alkoxyl, C.sub.1-6 alkoxycarbonyl, carboxyl, cyano-group, nitryl,
amino-group, --NR.sup.11--, methyl polyhalide, methoxyl polyhalide,
methylthio polyhalide, --S(.dbd.O).sub.pR.sup.12,
--NH--S(.dbd.O).sub.pR.sup.12, --C(.dbd.O)R.sup.12, --NHC(.dbd.O)H,
--C(.dbd.O)NHNH.sub.2, --NHC(.dbd.O)R.sup.12, and
--C(.dbd.NH)R.sup.12; Z and Y respectively are separately selected
from --NR.sup.11--, --NH--, --NH--NH--, --N.dbd.N--, --O--,
--C(.dbd.O)--, C.sub.1-4 alkanediyl, --CH(OH)--, --S--,
--S(.dbd.O)p--, -X.sub.2-C.sub.1-4 alkanediyl, -C.sub.1-4
alkanediyl-X.sub.2-, and --CH(CN)--; X.sub.2 is selected from
--NR.sup.11--, --NH--NH--, --N.dbd.N--, --O--, --C(.dbd.O)--,
--CH(OH)--, and --S(.dbd.O)p--; R.sup.11 is separately selected
from aryl, formoxyl, C.sub.1-6 alkycarbonyl, C.sub.1-6 alkyl,
C.sub.1-6 alkoxycarbonyl, C.sub.1-6 alkyl substituted by formoxyl,
C.sub.1-6 alkycarbonyl, C.sub.1-6 alkoxycarbonyl or C.sub.1-6
alkycarboxyl, C.sub.1-6 alkoxyl and C.sub.1-6 alkoxycarbonyl
substituted by C.sub.1-6 alkoxycarbonyl; R.sup.12 is selected from
C.sub.1-4 alkyl, amino-group, mono- or di-(C.sub.1-4 alkyl)
amino-group and C.sub.1-4 alkyl polyhalide. m is an integer from 0
to 5, n is an integer from 0 to 6; and P is an integer of 1 or
2.
15. The method of claim 14, wherein the reaction of step (a) is
under the protection of inert gas, wherein the inert gas is argon,
nitrogen, helium, or combinations thereof.
16. The method of claim 14, wherein the aprotic solvent used in
step (a) is acetonitrile, N,N-dimethylformamide,
N,N-dimethylacetamide, tetrahydrofuran, or combinations
thereof.
17. The method of claim 14, wherein bases used in step (a) are
selected from potassium carbonate, sodium carbonate, cesium
carbonate, sodium hydride, sodium hydroxide, and potassium
hydroxide.
Description
FIELD OF THE INVENTION
The present invention belongs to the technical field of medicament,
and specifically relates to a pyrimidine derivative, its
phamaceutically accepted salts, its hydrates and solvates, its
polycrystalline and eutectics, its precursors and derivatives of
the same biological function, and the preparation method and use
thereof.
BACKGROUND ARTS
AIDS, i.e. acquired immune deficiency syndrome, is an epidemic
caused by human immunodeficiency virus (HIV). During the process of
HIV's reverse transcription from mRNA to DNA, reverse transcriptase
(RT) performs a decisive function, and therefore becomes an
important target for the design of anti-AIDS medicines.
Among the current studies of anti-HIV medicines, non-nucleoside
reverse transcriptase inhibitors (NNRTIs) have become one of the
hotspots in the field of pharmaceutical chemistry for the benefits
of high efficiency and low toxicity and etc thereof. At present, 4
kinds of reverse transcriptase inhibitors have received FDA
approval: Nevirapine, Delavirdine, Efavirenz and etravirine
(TMC125). In addition, .alpha.-APA089439, HBY097 and TMC-278 are
undergoing clinical studies. Classical NNRTIs are only effective
against HIV-1, but ineffective against HIV-2.
Therefore, this field urgently needs a novel medicine to prevent or
treat AIDS.
SUMMARY OF THE INVENTION
The present invention aims at providing a pyrimidine derivative,
and the preparation method and use thereof.
One aspect of the present invention provides a diaryl pyrimidine
derivative or pharmaceutically acceptable salts thereof; the diaryl
pyrimidine derivative has the structure shown as the formula I:
##STR00002##
wherein: -a.sup.1=a.sup.2-a.sup.3=a.sup.4- represents the structure
of a divalent free radical: --CH.dbd.CH--CH.dbd.CH--,
--N.dbd.CH--CH.dbd.CH--, --CH.dbd.N--CH.dbd.CH--,
--N.dbd.N--CH.dbd.CH--, --N.dbd.CH--N.dbd.CH--,
--N.dbd.CH--CH.dbd.N--;
-b.sup.1=b.sup.2-b.sup.3=b.sup.4- represents the structure of a
divalent free radical: --CH.dbd.CH--CH.dbd.CH--,
--N.dbd.CH--CH.dbd.CH--, --N.dbd.N--CH.dbd.CH--,
--N.dbd.CH--N.dbd.CH--, --N.dbd.CH--CH.dbd.N--;
R.sup.1 and R.sup.2 respectively are separately selected from
hydrogen, hydroxyl, halogen, substituted C.sub.1-4 alkyl,
substituted C.sub.2-6 alkenyl, substituted C.sub.2-6 alkynyl,
C.sub.1-6 alkoxyl, cyano-group, nitryl, amino-group, --NH(OH)--,
--N(R.sup.6)p--;
R.sup.13 and R.sup.14 respectively are separately selected from
hydrogen, hydroxyl, halogen, substituted C.sub.1-4 alkyl,
substituted C.sub.2-6 alkenyl, substituted C.sub.2-6 alkynyl,
C.sub.1-6 alkoxyl, cyano-group, nitryl, amino-group, --NH(OH)--,
--N(R.sup.6)p--;
R.sup.3 and R.sup.4 respectively are separately selected from
hydrogen, hydroxyl, halogen, optionally C.sub.1-4 alkyl substituted
by cyano-group or --C(.dbd.O)R.sup.6, C.sub.3-7 cycloalkyl,
optionally C.sub.2-6 alkenyl substituted by one or more halogen
atoms or cyano-groups, optionally C.sub.2-6 alkynyl substituted by
one or more halogen atoms or cyano-groups, C.sub.1-6 alkoxyl,
C.sub.1-6 alkoxycarbonyl, carboxyl, cyano-group, nitryl,
amino-group, --NR.sup.5--, methyl polyhalide, methoxyl polyhalide,
methylthio polyhalide, --S(.dbd.O).sub.pR.sup.7,
--NH--S(.dbd.O).sub.pR.sup.7, --C(.dbd.O)R.sup.7, --NHC(.dbd.O)H,
--C(.dbd.O)NHNH.sub.2, --NHC(.dbd.O)R.sup.7,
--C(.dbd.NH)R.sup.7;
R.sup.5 represents hydrogen, C.sub.1-6 alkycarbonyl, aryl,
formoxyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxycarbonyl;
X and Y are separately selected from --NR.sup.6--, --NH--NH--,
--N.dbd.N--, --O--, --C(.dbd.O)--, C.sub.1-4 alkanediyl, --CHOH--,
--S--, --S(.dbd.O)p--, -X.sub.1-C.sub.1-4 alkanediyl- or
--C.sub.1-4 alkanediyl-X.sub.1-, --CH(CN)--;
X.sub.1 represents --NR.sup.6--, --NH--NH--, --N.dbd.N--, --O--,
--C(.dbd.O)--, --CHOH--, --S(.dbd.O)p--;
R.sup.6 is separately selected from hydrogen, aryl, formoxyl,
C.sub.1-6 alkycarbonyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxycarbonyl,
C.sub.1-6 alkyl substituted by formoxyl, C.sub.1-6 alkycarbonyl,
C.sub.1-6 alkoxycarbonyl or C.sub.1-6 alkycarboxyl, C.sub.1-6
alkoxyl or C.sub.1-6 alkoxycarbonyl substituted by C.sub.1-6
alkoxycarbonyl.
R.sup.7 is selected from C.sub.1-4 alkyl, amino-group-, --NH--NH--,
mono- or di-(C.sub.1-4 alkyl) amino-group of C.sub.1-4 alkyl
polyhalide.
m is an integer from 0 to 5, n is an integer from 0 to 6;
P is an integer of 1 or 2.
In another preferred embodiment, the diaryl pyrimidine derivative
has the structure shown as the formula II:
##STR00003##
In another preferred embodiment, the diaryl pyrimidine derivative
has the structure shown as the formula III:
##STR00004##
The diaryl pyrimidine derivative or the pharmaceutically acceptable
salts thereof according to the present invention, the salts are
selected from hydrochloride, sulfate, tartrate, citrate, fumarate,
or malate.
The second aspect of the present invention provides a diaryl benzo
pyrimidine derivative, N-oxides thereof, stereoisomerides, mixture
of stereoisomerides, or pharmaceutically acceptable salts, the
diaryl benzo pyrimidine derivative has the structure shown as the
formula IV.
##STR00005##
wherein R.sup.8 is independently selected from aryl, naphthyl,
substituted naphthyl, 5- or 6-membered aromatic heterocyclic,
C.sub.1-6 alkoxycarbonyl, aryloxycarbonyl, or substituted
aryloxycarbonyl.
R.sup.9 and R.sup.10 respectively are separately selected from
hydrogen, hydroxyl, halogen, C.sub.1-6 alkoxyl, C.sub.1-6
alkoxycarbonyl, carboxyl, cyano-group, nitryl, amino-group,
--NR.sup.11--, methyl polyhalide, methoxyl polyhalide, methylthio
polyhalide, --S(.dbd.O).sub.pR.sup.12,
--NH--S(.dbd.O).sub.pR.sup.12, --C(.dbd.O)R.sup.12, --NHC(.dbd.O)H,
--C(.dbd.O)NHNH.sub.2, --NHC(.dbd.O)R.sup.12,
--C(.dbd.NH)R.sup.12.
Z and Y respectively are separately selected from --NR.sup.11--,
--NH--, --NH--NH--, --N.dbd.N--, --O--, --C(.dbd.O)--, C.sub.1-4
alkanediyl, --CH(OH)--, --S--, --S(.dbd.O)p--, -X.sub.2-C.sub.1-4
alkanediyl or -C.sub.1-4 alkanediyl-X.sub.2-, --CH(CN)--;
X.sub.2 is selected from --NR.sup.11--, --NH--NH--, --N.dbd.N--,
--O--, --C(.dbd.O)--, --CH(OH)--, --S(.dbd.O)p--;
R.sup.11 is separately selected from hydrogen, aryl, formoxyl,
C.sub.1-6 alkycarbonyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxycarbonyl,
C.sub.1-6 alkyl substituted by formoxyl, C.sub.1-6 alkycarbonyl,
C.sub.1-6 alkoxycarbonyl or C.sub.1-6 alkycarboxyl, C.sub.1-6
alkoxyl or C.sub.1-6 alkoxycarbonyl substituted by C.sub.1-6
alkoxycarbonyl;
R.sup.12 is selected from C.sub.1-4 alkyl, amino-group, mono- or
di-(C.sub.1-4 alkyl) amino-group or C.sub.1-4 alkyl polyhalide.
m is an integer from 0 to 5, n is an integer from 0 to 6;
P is an integer of 1 or 2.
The pharmaceutically acceptable salts of the diaryl benzo
pyrimidine derivative according to the present invention, the
pharmaceutically acceptable salts are selected from hydrochloride,
sulfate, tartrate, citrate, fumarate, or malate.
The third aspect of the present invention provides a method for
preparing a diaryl pyrimidine derivative, comprising the following
steps:
(a) 4-chloro benzo pyrimidine derivative, substituted phenol or
aniline, and polar aprotic solvent are mixed together to react
according to the following general equation to obtain the diaryl
benzo pyrimidine derivative;
##STR00006##
or, the process comprises the steps of:
(i) 2-chloro benzo pyrimidine derivative and substituted phenol or
aniline are heated to 150.degree. C.-210.degree. C. to fuse to
react according to the following general equation, to obtain the
diaryl benzo pyrimidine derivative;
##STR00007##
wherein, R.sup.8 is separately selected from aryl, substituted
aryl, naphthyl, substituted naphthyl, 5- or 6-membered aromatic
heterocyclic, C.sub.1-6 alkoxycarbonyl, aryloxycarbonyl, or
substituted aryloxycarbonyl.
R.sup.9 and R.sup.10 respectively are separately selected from
hydrogen, hydroxyl, halogen, C.sub.1-6 alkoxyl, C.sub.1-6
alkoxycarbonyl, carboxyl, cyano-group, nitryl, amino-group,
--NR.sup.11--, methyl polyhalide, methoxyl polyhalide, methylthio
polyhalide, --S(.dbd.O).sub.pR.sup.12,
--NH--S(.dbd.O).sub.pR.sup.12, --C(.dbd.O)R.sup.12, --NHC(.dbd.O)H,
--C(.dbd.O)NHNH.sub.2, --NHC(.dbd.O)R.sup.12,
--C(.dbd.NH)R.sup.12.
Z and Y respectively are separately selected from --NR.sup.11--,
--NH--, --NH--NH--, --N.dbd.N--, --O--, --C(.dbd.O)--, C.sub.1-4
alkanediyl, --CH(OH)--, --S--, --S(.dbd.O)p--, -X.sub.2-C.sub.1-4
alkanediyl or -C.sub.1-4 alkanediyl-X.sub.2-, --CH(CN)--;
X.sub.2 is selected from --NR.sup.11--, --NH--NH--, --N.dbd.N--,
--O--, --C(.dbd.O)--, --CH(OH)--, --S(.dbd.O)p--;
R.sup.11 is separately selected from hydryogen, aryl, formoxyl,
C.sub.1-6 alkycarbonyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxycarbonyl,
C.sub.1-6 alkyl substituted by formoxyl, C.sub.1-6 alkycarbonyl,
C.sub.1-6 alkoxycarbonyl or C.sub.1-6 alkycarboxyl, C.sub.1-6
alkoxyl or C.sub.1-6 alkoxycarbonyl substituted by C.sub.1-6
alkoxycarbonyl;
R.sup.12 is selected from C.sub.1-4 alkyl, amino-group, mono- or
di-(C.sub.1-4 alkyl) amino-group or C.sub.1-4 alkyl polyhalide.
m is an integer from 0 to 5, n is an integer from 0 to 6;
P is an integer of 1 or 2.
In another preferred embodiment, the reaction of step (a) is
carried out under the protection of inert gas; the inert gas is
argon, nitrogen, helium, or combinations thereof.
In another preferred embodiment, the aprotic solvent used in step
(a) is acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide,
tetrahydrofuran, or combinations thereof.
In another preferred embodiment, bases is added during the reaction
of step (a); the base is potassium carbonate, sodium carbonate,
cesium carbonate, sodium hydride, sodium hydroxide, or potassium
hydroxide.
The fourth aspect of the present invention provides a
pharmaceutical composition; the pharmaceutical composition
comprises effective dosage of diaryl pyrimidine derivative provided
in the present invention or the pharmaceutically acceptable salts
thereof; and pharmaceutically acceptable carriers.
The fifth aspect of the present invention provides a pharmaceutical
composition; the pharmaceutical composition comprises effective
dosage of diaryl benzo pyrimidine derivative provided in the
present invention, N-oxides, stereoisomerides, mixture of
stereoisomerides, or pharmaceutically acceptable salts thereof; and
pharmaceutically acceptable carriers.
The sixth aspect of the present invention provides a use of the
diaryl pyrimidine derivative provided in the present invention or
the pharmaceutically acceptable salts thereof, for the
manufacturing of a medicament for prevention or treatment of
AIDS.
The seventh aspect of the present invention provides a use of the
diaryl benzo pyrimidine derivative provided in the present
invention, N-oxides, stereoisomerides, mixture of stereoisomerides,
or pharmaceutically acceptable salts thereof, for the manufacturing
of a medicament for prevention or treatment of AIDS.
Hereby, the present invention provides novel drugs to prevent or
treat AIDS.
DETAILED DESCRIPTION OF THE INVENTION
Through intensive study, the inventor performed reorganization to
the diaryl pyrimidine derivatives (DAPY), and simulated the action
model and structure-activity relationship of such kind of inhibitor
with HIV-1 RT, by means of computer aided drug design, here by to
guide further structure improvement. Naphthyl group is introduced
to C4-position of pyrimidine ring, to strengthen the .pi.-.pi.
accumulation between the inhibitor and the surrounding residues of
amino acids, Tyr188, Tyr181, Trp229, and Tyr318. Meanwhile,
substitutional groups are introduced to C5-, C6-positions of
pyrimidine ring, to strengthen its synergistic effect with naphthyl
ring, and to disturb the catalytic function of the surrounding
residues of amino acids. A series of diaryl pyrimidine derivatives
are prepared and the biological activities thereof are tested. The
results showed that most of the compounds have strong activities of
anti HIV-1, and high selectivity index, and a part of the compounds
show good inhibition activity against drug-resistant viral strain
of L103N+Y181C.
The present invention provides a diaryl pyrimidine derivative or
pharmaceutically acceptable salts thereof; the diaryl pyrimidine
derivative has the structure shown as the formula I:
##STR00008##
Preferably, the diaryl pyrimidine derivative provided in the
present invention has the structure shown as the formula II:
##STR00009##
wherein, -a.sup.1=a.sup.2-a.sup.3=a.sup.4- represents the structure
of a divalent free radical: --CH.dbd.CH--CH.dbd.CH--,
--N.dbd.CH--CH.dbd.CH--, --CH.dbd.N--CH.dbd.CH--,
--N.dbd.N--CH.dbd.CH--, --N.dbd.CH--N.dbd.CH--,
--N.dbd.CH--CH.dbd.N--;
-b.sup.1=b.sup.2-b.sup.3=b.sup.4- represents the structure of a
divalent free radical: --CH.dbd.CH--CH.dbd.CH--,
--N.dbd.CH--CH.dbd.CH--, --N.dbd.N--CH.dbd.CH--,
--N.dbd.CH--N.dbd.CH--, --N.dbd.CH--CH.dbd.N--;
R.sup.1 and R.sup.2 respectively are separately selected from
hydrogen, hydroxyl, halogen, substituted C.sub.1-4 alkyl,
substituted C.sub.2-6 alkenyl, substituted C.sub.2-6 alkynyl,
C.sub.1-6 alkoxyl, cyano-group, nitryl, amino-group, --NH(OH)--,
--N(R.sup.6)p--;
R.sup.13 and R.sup.14 respectively are separately selected from
hydrogen, hydroxyl, halogen, substituted C.sub.1-4 alkyl,
substituted C.sub.2-6 alkenyl, substituted C.sub.2-6 alkynyl,
C.sub.1-6 alkoxyl, cyano-group, nitryl, amino-group, --NH(OH)--,
--N(R.sup.6)p--;
R.sup.13 and R.sup.14 respectively are separately selected from
hydrogen, hydroxyl, halogen, substituted C.sub.1-4 alkyl,
substituted C.sub.2-6 alkenyl, substituted C.sub.2-6 alkynyl,
C.sub.1-6 alkoxyl, cyano-group, nitryl, amino-group, --NH(OH)--,
--N(R.sup.6)p--;
R.sup.3 and R.sup.4 respectively are separately selected from
hydrogen, hydroxyl, halogen, optionally C.sub.1-4 alkyl substituted
by cyano-group or --C(.dbd.O)R.sup.6, C.sub.3-7 cycloalkyl,
optionally C.sub.2-6 alkenyl substituted by one or more halogen
atoms or cyano-groups, optionally C.sub.2-6 alkynyl substituted by
one or more halogen atoms or cyano-groups, C.sub.1-6 alkoxyl,
C.sub.1-6 alkoxycarbonyl, carboxyl, cyano-group, nitryl,
amino-group, --NR.sup.5--, methyl polyhalide, methoxyl polyhalide,
methylthio polyhalide, --S(.dbd.O).sub.pR.sup.7,
--NH--S(.dbd.O).sub.pR.sup.7, --C(.dbd.O)R.sup.7, --NHC(.dbd.O)H,
--C(.dbd.O)NHNH.sub.2, --NHC(.dbd.O)R.sup.7,
--C(.dbd.NH)R.sup.7;
R.sup.5 represents hydrogen, C.sub.1-6 alkycarbonyl, aryl,
formoxyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxycarbonyl;
X and Y are separately selected from --NR.sup.6--, --NH--NH--,
--N.dbd.N--, --O--, --C(.dbd.O)--, C.sub.1-4 alkanediyl, --CHOH--,
--S--, --S(.dbd.O)p--, -X.sub.1-C.sub.1-4 alkanediyl- or -C.sub.1-4
alkanediyl-X.sub.1-, --CH(CN)--;
X.sub.1 represents --NR.sup.6--, --NH--NH--, --N.dbd.N--, --O--,
--C(.dbd.O)--, --CHOH--, --S(.dbd.O)p--;
R.sup.6 is separately selected from hydrogen, aryl, formoxyl,
C.sub.1-6 alkycarbonyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxycarbonyl,
C.sub.1-6 alkyl substituted by formoxyl, C.sub.1-6 alkycarbonyl,
C.sub.1-6 alkoxycarbonyl or C.sub.1-6 alkycarboxyl, C.sub.1-6
alkoxyl or C.sub.1-6 alkoxycarbonyl substituted by C.sub.1-6
alkoxycarbonyl.
R.sup.7 is selected from C.sub.1-4 alkyl, amino-group-, --NH--NH--,
mono- or di-(C.sub.1-4 alkyl) amino-group of C.sub.1-4 alkyl
polyhalide.
m is an integer from 0 to 5, n is an integer from 0 to 6;
P is an integer of 1 or 2.
The method for preparing the compound shown as the formula II is as
following:
(1) A diaryl pyrimidine derivative wherein R.sup.1 is H, Cl,
C.sub.1-4 alkyl, C.sub.2-6 alkynyl, C.sub.2-6 alkenyl is prepared
according to the reference (CN200710045937.0), and the general
equation is as following:
##STR00010##
(2) The diaryl pyrimidine derivative wherein R.sup.1 is C.sub.1-6
alkoxyl is prepared with the diaryl pyrimidine derivative
substituted by Cl as the reactant to react with C.sub.1-6 sodium
alkoxide, the reaction equation is as following:
##STR00011##
(3) The diaryl pyrimidine derivative wherein R.sup.1 is amino-group
or --N(R.sup.6)p-- (p=1,2) is prepared with the diaryl pyrimidine
derivative substituted by Cl as reactant to react with alkanamine
individually, the reaction equation is as following:
##STR00012## The compound shown as the formula II is an easily
synthesized and completely novel anti-HIV reagent, and may be used
as a candidate anti-HIV drug. The biological activity in the level
of cells showed that: (1) this type of compounds generally possess
good anti-HIV activity, and a part of the compounds not only show
biological activity on nmol level, but also show high selectivity
index. (2) Among the synthesized compounds, a part of the compounds
show good inhibition activity against drug-resistant viral strain
of L103N+Y181C.
More preferably, the diaryl pyrimidine derivative synthesized in
the present invention has the structure shown as the formula
III:
##STR00013##
wherein, R.sup.13 and R.sup.14 respectively are separately selected
from hydrogen, hydroxyl, halogen, substituted C.sub.1-4 alkyl,
substituted C.sub.2-6 alkenyl, substituted C.sub.2-6 alkynyl,
C.sub.1-6 alkoxyl, cyano-group, nitryl, amino-group, --NH(OH)--,
--N(R.sup.6)p--;
X is selected from --NR.sup.6--, --NH--NH--, --N.dbd.N--, --O--,
--C(.dbd.O)--, C.sub.1-4 alkanediyl, --CHOH--, --S--,
--S(.dbd.O)p--, -X.sub.1-C.sub.1-4 alkanediyl- or -C.sub.1-4
alkanediyl-X.sub.1-, --CH(CN)--;
X.sub.1 is selected from --NR.sup.6--, --NH--NH--, --N.dbd.N--,
--O--, --C(.dbd.O)--, --CHOH--, --S(.dbd.O)p--;
R.sup.6 is separately selected from hydrogen, aryl, formoxyl,
C.sub.1-6 alkycarbonyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxycarbonyl,
C.sub.1-6 alkyl substituted by formoxyl, C.sub.1-6 alkycarbonyl,
C.sub.1-6 alkoxycarbonyl or alkycarboxyl, C.sub.1-6 alkoxyl or
C.sub.1-6 alkoxycarboxyl substituted by C.sub.1-6
alkoxycarboxyl.
P is an integer of 1 or 2.
The method for preparing the compound shown as the formula III is
as following:
(1) R.sup.13 and R.sup.14 are H, Cl, C.sub.1-4 alkyl, C.sub.2-6
alkynyl, C.sub.2-6 alkenyl respectively. The diaryl pyrimidine
derivative, wherein X is O, is prepared according to the reference
(CN200710045937.0); the general reaction equation is as
following:
##STR00014##
i.e., under the protection of inert gas, substituted naphthol is
added to anhydrous aprotic solvent and agitated to dissolve, then
4-chloro pyrimidine derivative is added and agitated to dissolve,
after the addition of anhydrous K.sub.2CO.sub.3, the temperature is
controlled at 90.about.100.degree. C., the system is agitated to
keep reaction for 8.about.12 h. When TLC shows that the reaction is
complete, K.sub.2CO.sub.3 is filtered out, and the filtrate is
poured into cold water, the crystal is filtered out and dried. The
desired compound is achieved by recrystallization with toluene or
dioxane and etc., or by column chromatography.
(2) R.sup.13 and R.sup.14 are H, Cl, C.sub.1-4 alkyl, C.sub.2-6
alkynyl, C.sub.2-6 alkenyl respectively; the general reaction
equation of preparing the diaryl pyrimidine derivative wherein X is
nitrogen is as following:
##STR00015##
Substituted naphthylamine is dissolved in DMF, then 4-chloro
pyrimidine is added and agitated to dissolve, and heated under
reflux for 20 h in an oil bath at 150.degree. C., the reaction
mixture is poured into cold water and the deposited solid is
filtered out and dried. The desired compound is obtained by
recrystallization with toluene or dioxane and etc., or by column
chromatography.
The compound shown as the formula III is an easily synthesized and
completely novel anti-HIV reagent, and may be used as a candidate
anti-HIV drug. The biological activity in the level of cells showed
that: (1) this type of compounds generally possess good anti-HIV
activity, and a part of the compounds not only show biological
activity on nmol level, but also show high selectivity index. (2)
Among the synthesized compounds, a part of the compounds show good
inhibition activity against drug-resistant viral strain of
L103N+Y181C.
Therefore, the present invention provides a pharmaceutical
composition, the composition consists effective dosage of the
diaryl pyrimidine derivative shown as the formula I, II, or III, or
pharmaceutically acceptable salts thereof; and pharmaceutically
acceptable carriers.
As used herein, the terms of "containing" or "comprising" comprise
"including", "basically be consisted of", and "be consisted
of".
As used herein, the components of the term of "pharmaceutically
acceptable" or "bromatologically acceptable" are those suitable to
human and/or animals without excess adverse-effect (such as
toxicity, irritant and allergic reaction), i.e. the substances
possessing reasonable ratio of benefits and risk.
As used herein, the term of "effective dosage" refers to the amount
that is sufficient to achieve the desired function or activity on
human and/or animal and can be accepted by human and/or animal.
As used herein, the term of "pharmaceutically acceptable carriers"
refers to the carriers of medicaments, including all kinds of
excipients and diluents. The term refers to such kinds of carriers:
they are not necessary active components, and possessing no excess
toxicity after application. Suitable carriers are well known to
those skilled in the art. Full discussion on pharmaceutically
acceptable carriers can be found in Remington's Pharmaceutical
Sciences (Mack Pub. Co., N.J. 1991). The pharmaceutically
acceptable carriers used in the pharmaceutical compositions can be
liquid, such as water, brine, glycerol and alcohol. Additionally,
auxiliary substances can be existed in the carriers, such as
fillers, disintegrating agents, lubricants, flow aids, effervescent
agents, wetting agents or emulsifiers, corrigents, pH buffer
substances and etc.
The present invention provides a diaryl benzo pyrimidine
derivative, N-oxides, stereoisomerides, mixture of
stereoisomerides, or pharmaceutically acceptable salts thereof, the
diaryl benzo pyrimidine derivative has the structure shown as the
formula IV:
##STR00016##
wherein R.sup.8 is independently selected from aryl, substituted
aryl, naphthyl, substituted naphthyl, 5- or 6-membered aromatic
heterocyclic, C.sub.1-6 alkoxycarbonyl, aryloxycarbonyl, or
substituted aryloxycarbonyl;
R.sup.9 and R.sup.10 respectively are separately selected from
hydrogen, hydroxyl, halogen, C.sub.1-6 alkoxyl, C.sub.1-6
alkoxycarbonyl, carboxyl, cyano-group, nitryl, amino-group,
--NR.sup.11--, methyl polyhalide, methoxyl polyhalide, methylthio
polyhalide, --S(.dbd.O).sub.pR.sup.12,
--NH--S(.dbd.O).sub.pR.sup.12, --C(.dbd.O)R.sup.12, --NHC(.dbd.O)H,
--C(.dbd.O)NHNH.sub.2, --NHC(.dbd.O)R.sup.12,
--C(.dbd.NH)R.sup.12;
Z and Y respectively are separately selected from --NR.sup.11--,
--NH--, --NH--NH--, --N.dbd.N--, --O--, --C(.dbd.O)--, C.sub.1-4
alkanediyl, --CH(OH)--, --S--, --S(.dbd.O)p--, -X.sub.2-C.sub.1-4
alkanediyl or -C.sub.1-4 alkanediyl-X.sub.2-, --CH(CN)--;
X.sub.2 is selected from --NR.sup.11--, --NH--NH--, --N.dbd.N--,
--O--, --C(.dbd.O)--, --CH(OH)--, --S(.dbd.O)p--;
R.sup.11 is separately selected from hydrogen, aryl, formoxyl,
C.sub.1-6 alkycarbonyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxycarbonyl,
C.sub.1-6 alkyl substituted by formoxyl, C.sub.1-6 alkycarbonyl,
C.sub.1-6 alkoxycarbonyl or C.sub.1-6 alkycarboxyl, C.sub.1-6
alkoxyl or C.sub.1-6 alkoxycarbonyl substituted by C.sub.1-6
alkoxycarbonyl;
R.sup.12 is selected from C.sub.1-4 alkyl, amino-group, mono- or
di-(C.sub.1-4 alkyl) amino-group or C.sub.1-4 alkyl polyhalide;
m is an integer from 0 to 5, n is an integer from 0 to 6;
P is an integer of 1 or 2.
The method for preparing the compound shown as the formula III is
as following:
Method One:
4-chloro benzo pyrimidine derivative is reacted with the
corresponding substituted phenol (or phenylamine and etc.) under
the exsistence of K.sub.2CO.sub.3 to obtain the product of the
present invention, the general reaction equation is as
following:
##STR00017##
The detailed steps are as following: under the protection of inert
gas, substituted phenol (or phenylamine and etc.) is added to
anhydrous aprotic solvent and agitated to dissolve, then 4-chloro
benzo pyrimidine derivative is added and agitated to dissolve,
after the addition of anhydrous potassium carbonate, the system is
agitated to keep reaction for 8.about.12 h at 80.about.120.degree.
C. When TLC shows that the reaction is complete, K.sub.2CO.sub.3 is
filtered out, and the filtrate is poured into cold water, the
crystal is filtered out and dried. The desired compound is obtained
through decoloring by activated carbon and recrystallization with
toluene.
More preferably, the molar ratio of 4-chloro benzo pyrimidine
derivative and substituted phenol (or phenylamine and etc.) is
1:1.2.about.1:1.5. Anhydrous K.sub.2CO.sub.3 should be greatly
excess, approximately be 5 times of the amount of substituted
phenol; the aprotic solvent is DMF, DEA, acetonitrile; 1 mmol
4-chloro benzo pyrimidine derivative needs 6.about.8 mL aprotic
solvent; the inert gas is nitrogen, argon and etc.
Method Two:
2-chloro benzo pyrimidine derivative is reacted with the
corresponding substituted phenol (or phenylamine and etc.) in
solvent-free conditions to obtain the product of the present
invention; the general reaction equation is as following:
##STR00018##
The detailed steps are as following: substituted phenol (or
phenylamine and etc.) are mixed together, and heated to 150.degree.
C.-210.degree. C. until the reactants are completely fused, and
kept reaction for 1 h. When TLC shows that the reaction is
complete, the reaction mixture is dissolved in DMF, decolored with
activated carbon, and filtered, the filtrate is poured into cold
water. The solid is filtered out and dried. The desired compound is
obtained through recrystallization with toluene.
The compound shown as the formula IV is an easily synthesized and
completely novel anti-HIV reagent, and may be used as a candidate
anti-HIV drug. The biological activity in the level of cells showed
that: this type of compounds generally possesses good anti-HIV
activity, and a part of the compounds not only show biological
activity on nmol level, but also show high selectivity index.
Therefore, the present invention provides a pharmaceutical
composition, the composition comprises effective amount of the
diaryl benzo pyrimidine derivative shown as the formula IV,
N-oxides, stereoisomerides, mixture of stereoisomerides, or
pharmaceutically acceptable salts therefore; and pharmaceutically
acceptable carriers.
The characteristics mentioned in the present invention or in the
embodiments can be free to combine.
The main benefits of the present invention are as follows:
1. The compound provided in the present invention possesses novel
structure, and good anti HIV biological activity, and slight cell
toxicity.
2. The preparation method of the compound provided in the present
invention is easy, and can be further developed as anti-AIDS
drugs.
The present invention will be further explained in respect of the
various embodiments below. It is to be understood that the
embodiments serve to explain only, without limitation the scope of
the present invention. The experimental processes of the following
embodiments where the conditions are not listed should be carried
out generally according to the regular conditions or according to
the suggested conditions by manufacturers. Unless specifically
stated to the contrary, percents, ratios, proportions, or parts
herein are all by weight.
The units of the weight volume percent herein are familiar to those
skilled in the art, such as applied to refer to the weight of the
solute in 100 mL solution.
Unless specifically defined to the contrary, all the specialized or
scientific terms herein possess the same meaning as that known to
those skilled in the art. Additionally, any process or material
similar or equivalent to the records can be applied in the process
of the present invention. The preferred embodiments and materials
herein serve to demonstrate only.
Anti-HIV Biological Activity Test in the Embodiments of the Present
Invention
Anti-virus activity of cells in vitro was determined by Rega
Institute for Medical of Spain Katholleke University, consisting
mainly: inhibitory activity towards HIV-infected MT-4 cells and
cell toxicity. The method is described below: exert the compound on
the HIV-infected ME-4 cells, and determine the protection of the
drug on the cell lesions induced by HIV at varied HIV-infection
intervals, calculate the half effective concentration IC.sub.50,
the required concentration that protect 50% of cells from cell
lesions induced by HIV. Toxicity determination is carried out in
parallel with anti-HIV activity experiments, also in the cultured
MT-4 cells, determine the CC.sub.50, the concentration that leads
50% of uninfected cells to cell lesions, and calculate the
selectivity index SI=CC.sub.50/IC.sub.50 with the MTT method.
Materials and Methods
Anti-HIV activity of various compounds is monitored by the
inhibitory efficiency of drugs on the cell lesions induced by HIV.
Carry out cell culture with MT-4 cells. The adopted virus strains
are HIV-1 IIIB strain and drug-resistant viral strain of
L103N+Y181C.
The detailed operation is as follows: the compound is dissolved
with DMSO or water and diluted with phosphate buffer saline,
3.times.10.sup.5 MT-4 cells are cultured with 100 .mu.L various
concentrations of compounds for 1 h, then 100 .mu.L suitable virus
dilution is added to the compound, and the cells are cultured at
37.degree. C. for 1 h. After being washed for 3 times, the cells
are suspended again in the culture media containing or not
compounds individually. Subsequently, the cells are transferred to
the atmosphere containing 5% CO.sub.2 and cultured for 7 days at
37.degree. C., and culture media containing or not compounds are
used to replace or supplement the culture solution on the third day
after infection. Kinds of culture conditions should be duplicated.
The cell lesions caused by virus are monitored with reverse light
microscopy everyday. Typically, the virus dilution applied in the
present experiments generally cause cell lesion on the fifth day
after infection. Inhibitory concentration of a drug is expressed
with the concentration that is required for 50% inhibition of cell
lesions (EC.sub.50) caused by virus and meanwhile shows no direct
toxicity to cells (CC.sub.50). It should be emphasized that, when
the compound is poorly water-soluble and can only be dissolved in
DMSO, the ratio of DMSO to water is generally below 10% (the final
concentration of DMSO in MT-4 cell culture media is smaller than
2%). Because DMSO can influence the anti-virus activity of the
tested compounds, blank tests on the solution containing the same
concentration of DMSO should be conducted in parallel.
Additionally, the final concentration of DMSO is far below the
concentration required to influence the replication of HIV-1 in T
cells.
Example 1
Synthesis of the Diaryl Pyrimidine
Under the protection of inert gas, naphthol was added to anhydrous
aprotic solvent, and agitated to dwassolve, then 4-chloro
pyrimidine derivative was added and agitated to dissolve, after
addition of anhydrous K.sub.2CO.sub.3, the temperature was
controlled at 90.about.100.degree. C. and the system was agitated
to keep reaction for 8.about.12 h. When TLC shows that the reaction
was complete, K.sub.2CO.sub.3 was filtered out, and the filtrate
was poured into cold water, the deposited crystal was filtered out
and dried. The desired compound was obtained through decoloring by
activated carbon and recrystallization with toluene.
Target compounds were prepared by the above mentioned process with
various 4-chloro pyrimidine derivatives and various substituted
naphthols, parts of the results are as follows:
Under the protection of N.sub.2, 8-hydroxy quinoline (4.2 mmol) was
added to 30 mL anhydrous DMF and agitated to dissolve, then
2-(4-cyanoanilino)-4-chloro methyl pyrimidine (3.5 mmol) was added
and agitated for 10 min to dissolve, after addition of anhydrous
K.sub.2CO.sub.3 (0.021 mol), the temperature was controlled at
80.degree. C. and the system was agitated to keep reaction for 8 h.
When TLC shows that the reaction was complete, K.sub.2CO.sub.3 was
filtered out, and the filtrate was poured into 300 mL cold water,
solid was deposited; the solid was filtered out and dried and the
crude product was prepared. The desired compound 1 was achieved
through decoloring by activated carbon and recrystallization with
toluene.
##STR00019##
Brown powder, yield: 87%: mp: 178.6-181.5.degree. C.;
.sup.1HNMR(DMSO, 400 MHz) .delta..sub.ppm: 6.74(d, J=5.6Hz, 1H,
CH), 7.21-7.28(m, 4H, Ph), 7.57-8.83(m, 6H, Quin), 8.45(d, J=5.6Hz,
1H, CH), 9.98(s, 1H, NH).
Under the protection of N.sub.2, 8-hydroxy quinoline (5.2 mmol) was
added to 30 mL anhydrous acetonitrile and agitated to dissolve,
then 2-(4-Cyanoanilino)-4,6-dichloro pyrimidine (5.2 mmol) was
added and agitated for 10 min to dwassolve, after addition of
anhydrous K.sub.2CO.sub.3 (0.021 mol), the temperature was
controlled at 90.about.100.degree. C. and the system was agitated
to keep reaction for 8 h. When TLC shows that the reaction was
complete, K.sub.2CO.sub.3 was filtered out, and the filtrate was
poured into 300 mL cold water, solid was deposited; the solid was
filtered out and dried and the crude product was prepared. The
desired compound 2 was achieved through decoloring by activated
carbon and recrystallization with toluene.
##STR00020##
Green powder, yield: 85%; mp:138.4-141.4.degree. C.;
.sup.1HNMR(DMSO, 400 MHz) .delta..sub.ppm: 6.92(s, 1H, CH),
7.06-7.24(m, 4H, Ph), 7.55-8.82(m, 6H, Quin), 10.33(s, 1H, NH).
The prepared compound 2 (2 mmol) above was dissolve in 25 mL
dioxane, and agitated to dissolve, then 5 mL methylamine alcohol
solution was added, and the temperature was controlled at
140-150.degree. C., and the system was agitated to keep reaction
for 12 h. When TLC shows that the reaction was complete, compound 3
was achieved by recrystallization with water.
##STR00021## White powder, yield: 68%, mp: 231.4-232.1.degree. C.;
.sup.1HNMR(DMSO, 400 MHz) .delta..sub.ppm: 2.82(s, 3H, NHCH.sub.3),
5.50(s, 1H, CH), 7.20 (s, 1H, NHCH.sub.3), 7.34-7.79 (m, 4H, Ph),
7.48-8.72(m, 6H, Quin), 9.46(s, 1H, NH).
Sodium (10 mmol) was dissolved in 50 mL anhydrous methol, and
agitated to dissolve, then the prepared compound 2 was added, and
the temperature was controlled at 40-50.degree. C., the system was
agitated to keep reaction for 48 h. When TLC shows that the
reaction was complete, compound 4 was achieved by recrystallization
with water.
##STR00022##
White powder, yield: 92%; mp: 231.4-232.1.degree. C.;
.sup.1HNMR(DMSO, 400 MHz) .delta..sub.ppm: 3.92(s, 3H, OCH.sub.3),
6.02(s, 1H, CH), 7.17-7.32(m, 4H, Ph), 7.54-8.82(m, 6H, Quin),
9.87(s, 1H, NH).
Example 2
Synthesis of the Diaryl Pyrimidine Derivative
Under the protection of inert gas, substituted naphthol was added
to anhydrous aprotic solvent, and agitated to dissolve, then
4-chloro pyrimidine derivative was added and agitated to dissolve,
after addition of anhydrous K.sub.2CO.sub.3, the temperature was
controlled at 90.about.100.degree. C., the system was agitated to
keep reaction for 8.about.12 h. When TLC shows that the reaction
was complete, K.sub.2CO.sub.3 was filtered out, and the filtrate
was poured into 300 mL cold water, solid was deposited; the solid
was filtered out and dried. The desired compound was obtained
through column chromatography or recrystallization.
Target compounds were prepared by the above mentioned process with
4-chloro pyrimidine derivatives and various substituted naphthols;
parts of the results are as following:
Under the protection of N.sub.2, .beta.-naphthol derivative (4.2
mmol) was added to 30 mL anhydrous DMF, and agitated to dissolve,
then 2-(4-Cyanoanilino)-4-methyl pyrimidine (3.5 mmol) is added and
agitated for 10 min to dissolve, after addition of anhydrous
K.sub.2CO.sub.3, the temperature is controlled at
90.about.100.degree. C., the system was agitated to keep reaction
for 8 h. When TLC shows that the reaction was complete, the
filtrate was poured into 300 mL cold water, solid was deposited;
the solid was filtered out and dried and the crude product was
prepared. The desired compound 20 was achieved through column
separation.
##STR00023## White powder, yield: 89.3%; mp 249.2-250.1.degree.
C.;.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.90 (s, 3H,
CH.sub.3), 6.76 (d, 1H, J=4.0 Hz, CH), 7.25-7.55 (m, 4H, Ph),
7.64-8.50 (m, 5H, Naph), 8.71 (s, 1H, CH), 10.10 (s, 1H, NH);
.sup.13C NMR (400 MHz, DMSO-d.sub.6) .delta. 61.77, 99.70, 102.55,
108.66, 118.22, 118.99, 119.27, 123.33, 125.13, 126.97, 129.96,
131.14, 132.42, 143.19, 144.35, 146.29, 158.98, 160.42, 168.97. MS
(EI) m/z: 393.1 (M+); Anal. (C.sub.23H.sub.15N.sub.6O.sub.2) C, H,
N.
##STR00024## White powder, yield: 41.8%; mp 249.3-250.4.degree. C.;
.sup.1H NMR (400 MHz, DMSO-d.sub.6).delta. 3.85 (s, 3H, OCH.sub.3),
3.91 (s, 3H, OCH.sub.3), 6.78 (d, J=4.0Hz, 1H), 7.24-7.52 (m, 4H,
Ph), 7.54-8.54 (m, 4H, Naph), 8.49 (d, J=4.0Hz, 1H); .sup.13C NMR
(400 MHz, DMSO-d.sub.6) .delta. 56.83, 62.23, 99.77, 102.98,
104.10, 109.61, 118.62, 119.63, 119.76, 123.76, 125.20, 125.46,
131.61, 132.93, 133.28, 135.82, 144.87, 148.00, 153.19, 160.83,
169.18. MS (EI) m/z: 423.2 (M+); Anal.
(C.sub.24H.sub.17N.sub.5O.sub.3) C, H, N.
##STR00025## White powder, yield: 85.9%, mp 253.2-254.8
.quadrature.C;.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12
.sup.13C NMR (400 MHz, DMSO-d.sub.6) .delta. 3.83 (s, 3H,
OCH.sub.3), 6.69 (d, J=5.6Hz, .sup.1H), 7.28-7.67 (m, 4H, Ph),
7.54-8.52 (m, 5H, Naph), 8.45 (d, J=5.6Hz, 1H), 10, 07 (s, 1H, NH);
.sup.13C NMR (400 MHz, DMSO-d.sub.6) .delta. 56.63, 99.94, 102.97,
108.98, 109.02, 118.66, 119.79, 119.81, 121.34, 125.39, 129.25,
130.47. 131.98, 132.98, 133.04, 144.47, 144.92, 152.33, 159.40.
160.67, 169.56. MS (EI) m/z: 393.1 (M+); Anal.
(C.sub.23H.sub.15N.sub.6O.sub.2) C, H, N.
##STR00026## White powder, yield: 71.6%, mp 297.5-298.7
.quadrature.C;.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 6.82 (d,
J=4.0Hz, 1H), 7.27-7.52 (m, 4H, Ph), 8.02-8.54 (m, 5H, Naph), 8.82
(s, 1H, CH), 10.12 (s, 1H, NH); .sup.13C NMR (400 MHz,
DMSO-d.sub.6) .delta. 100.18, 103.15, 109.78, 118.81, 119.09,
119.72, 123.09, 125.27, 125.55, 129.19, 130.08, 131.49, 132.81,
132.93, 135.93, 144.72, 159.33, 161.18, 168.88. MS (EI) m/z: 393.1
(M+); Anal. (C.sub.22H.sub.12ClN.sub.5O) C, H, N, Cl.
##STR00027## White powder, yield: 33.4%, mp: 268.4-269.2
.quadrature.C;.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12
.sup.13C NMR (400 MHz, DMSO-d.sub.6) .delta. 3.89 (s, 3H,
CH.sub.3), 6.82 (d, J=4.4Hz, 1H), 7.25-7.49 (m, 4H, Ph), 7.82-8.63
(m, 4H, Naph), 8.52 (d, J=4.4Hz, 1H), 10.11 (s, 1H, NH); .sup.13C
NMR (400 MHz, DMSO-d.sub.6) .delta. 57.21, 99.71, 103.15, 108.27,
110.23, 118.66, 119.25, 119.72, 124.69, 125.54, 126.74, 127.57,
131.95, 132.94, 133.76, 141.45, 144.75, 152.66, 159.35, 161.13,
168.47. MS (EI) m/z: 427.1 (M+); Anal. (C.sub.23H14ClN.sub.5O2) C,
H, N, Cl.
Example 3-1
Synthesis of the Diaryl Benzo Pyrimidine Derivative (Method
One)
Under the protection of inert gas, substituted phenol (or
phenylamine and etc.) is added to aprotic solvent, and agitated to
dissolve, and then 4-choloro benzo pyrimidine derivative is added
and agitated to dissolve, after addition of anhydrous
K.sub.2CO.sub.3, the temperature is controlled at
80.about.120.degree. C. and the system was agitated to keep
reaction for 8.about.12 h. When TLC shows that the reaction was
complete, K.sub.2CO.sub.3 was filtered out, and the filtrate was
poured into cold water, the deposited crystal was filtered out and
dried. The desired compound was obtained through decoloring by
activated carbon and recrystallization with toluene.
Target compounds were prepared by the above mentioned process with
various 4-chloro pyrimidine derivatives and various substituted
phenols, parts of the results are as following:
Under the protection of N.sub.2, 2-methylphenol (4.2 mmol) was
added to 30 mL anhydrous DMF, and agitated to dissolve, then
2-(4-Cyanoanilino)-4-chloro benzo pyrimidine (3.5 mmol) was added
and agitated to dissolve, after addition of anhydrous
K.sub.2CO.sub.3 (0.021 mol), the temperature was controlled at
90.about.100.degree. C. and the system was agitated to keep
reaction for 8 h. When TLC shows that the reaction was complete,
K.sub.2CO.sub.3 was filtered out, and the filtrate was poured into
300 mL cold water, solid was deposited; the solid was filtered out
and dried. The desired compound was obtained through decoloring by
activated carbon and recrystallization with toluene.
##STR00028##
Brown powder, yield: 75% ; mp; 197.3-197.4.degree. C.; .sup.1HNMR
(DMSO-d.sub.6) .delta. (ppm) 2.16 (s, 3H, CH.sub.3), 7.30-7.44 (m,
4H, Ar'H), 7.49 (td, 1H, J=7.6 Hz, J'=1.2 Hz, ArH.sub.7), 7.56 (d,
2H, J=8.8 Hz, Ar''H.sub.2,6), 7.72 (d, 1H, J=8.4 Hz, ArH.sub.6),
7.86 (d, 2H, J=8.8 Hz, Ar''H.sub.3,5), 7.90 (td, 1H, J=7.6 Hz,
J'=1.2 Hz, ArH.sub.8), 8.27 (dd, 1H, J=8.0 Hz, J'=0.8 Hz,
ArH.sub.9), 10.04 (s, 1H, NH).
.sup.13C NMR (DMSO-d.sub.6) .delta. (ppm) 16.4 (CH.sub.3), 102.8
(Ar''C.sub.4), 112.2 (ArC.sub.5), 118.9 (2C, Ar''C.sub.2,6), 120.0
(CN), 122.9 (ArC.sub.6), 124.2 (Ar'C.sub.6), 124.8 (ArC.sub.7),
125.9 (ArC.sub.9), 126.7 (Ar'C.sub.4), 128.0 (Ar'C.sub.5), 130.7
(Ar'C.sub.3), 131.9 (ArC.sub.8), 133.1 (Ar'C.sub.2), 135.4 (2C,
Ar''C.sub.3,5), 145.4 (Ar''C.sub.1), 151.4 (Ar'C.sub.1), 153.1
(ArC.sub.10), 155.7 (ArC.sub.2), 167.2 (ArC.sub.4).
MS (ESI) m/z 353 (M.sup.++1).
##STR00029##
The operation was the same as above mentioned. Yellow acicular
crystal, yield: 85%; mp: 267.3-267.6.degree. C.; .sup.1H NMR
(DMSO-d.sub.6) .delta. (ppm) 7.41 (d, 2H, J=6.8 Hz, Ar''H.sub.2,6),
7.47 (t, 1H, J=7.2 Hz, ArH.sub.7), 7.61 (d, 2H, J=8.8 Hz,
Ar'H.sub.2,6), 7.71-7.75 (m, 3H, ArH.sub.6+Ar''H.sub.3,5), 7.88
(td, 1H, J=8.4 Hz, J'=1.2 Hz, ArH.sub.8), 7.94 (d, 2H, J=8.4 Hz,
Ar'H.sub.3,5), 8.21 (d, 1H, J=8.4 Hz, ArH.sub.9), 10.02 (s, 1H,
NH).
.sup.13C NMR (DMSO-d.sub.6) .delta. (ppm) 103.0 (Ar''C.sub.4),
112.5 (ArC.sub.5), 118.8 (2C, Ar''C.sub.2,6), 119.0 (2C,
Ar'C.sub.2,6), 120.0 (CN), 124.2 (Ar'C.sub.4), 124.8 (ArC.sub.6),
125.2 (2C, Ar'C.sub.3,5), 126.0 (ArC.sub.7), 133.1 (ArC.sub.9),
133.2 (2C, Ar''C.sub.3,5), 135.5 (ArC.sub.8), 145.3 (Ar''C.sub.1),
152.2 (ArC.sub.10), 153.1 (Ar'C.sub.1), 155.4 (ArC.sub.2), 167.4
(ArC.sub.4).
MS (ESI) m/z 417 (M.sup.++1).
##STR00030##
The operation was the same as above mentioned. White acicular
crystal solid, yield: 98.3%; mp:219.7-220.3.degree. C.; .sup.1H NMR
(DMSO-d.sub.6) .delta. (ppm) 2.39 (s, 3H, CH.sub.3), 7.18-7.22 (m,
3H, Ar'H), 7.43 (d, 1H, J=7.6 Hz, Ar'H), 7.48 (td, 1H, J=8.0 Hz,
J'=1.2 Hz, ArH.sub.7), 7.59 (d, 2H, J=8.4 Hz, Ar''H.sub.2,6), 7.72
(d, 1H, J=8.4 Hz, ArH.sub.6), 7.88 (td, 1H, J=7.2 Hz, J'=1.2 Hz,
ArH.sub.8), 7.93 (d, 2H, J=8.4 Hz, Ar''H.sub.3,5), 8.22 (dd, 1H,
J=8.4 Hz, J'=1.2 Hz, ArH.sub.9), 10.03 (s, 1H, NH).
.sup.13C NMR (DMSO-d.sub.6) .delta. (ppm) 20.8 (CH.sub.3), 102.3
(Ar''C.sub.4), 112.0 (ArC.sub.5), 118.4 (2C, Ar''C.sub.2,6), 119.0
(CN), 119.4 (ArC.sub.6), 122.4 (Ar'C.sub.6), 123.6 (Ar'C.sub.2),
124.1 (ArC.sub.7), 125.3 (ArC.sub.9), 126.5 (Ar'C.sub.4), 129.5
(Ar'C.sub.5), 132.6 (2C, Ar''C.sub.3,5), 134.8 (ArC.sub.8), 139.6
(Ar'C.sub.3), 144.8 (Ar''C.sub.1), 152.3 (ArC.sub.10), 152.5
(Ar'C.sub.1), 155.0 (ArC.sub.2), 167.1 (ArC.sub.4).
MS (ESI) m/z 353 (M.sup.++1).
##STR00031##
The operation was the same as above mentioned. White flocculus
solid, yield:89.1%; mp: 218.2-218.4.degree. C.; .sup.1H NMR
(DMSO-d.sub.6) .delta. (ppm) 3.83 (s, 3H, CH.sub.3O), 7.08 (d, 2H,
J=6.8 Hz, Ar'H.sub.3,5), 7.32 (d, 2H, J=6.8 Hz, Ar'H.sub.2,6), 7.47
(td, 1H, J=8.0 Hz, J'=0.8 Hz, ArH.sub.7), 7.59 (d, 2H, J=8.8 Hz,
Ar''H.sub.2,6), 7.71 (d, 1H, J=8.4 Hz, ArH.sub.6), 7.87 (td, 1H,
J=8.4 Hz, J'=1.2 Hz, ArH.sub.8), 7.95 (d, 2H, J=8.4 Hz,
Ar''H.sub.3,5), 8.21 (dd, 1H, J=8.4 Hz, J'=1.2 Hz, ArH.sub.9), 9.99
(s, 1H, NH).
.sup.13C NMR (DMSO-d.sub.6) .delta. (ppm) 56.0 (CH.sub.3O), 102.9
(Ar''C.sub.4), 112.6 (ArC.sub.5), 115.3 (2C, Ar'C.sub.3,5), 119.0
(2C, Ar''C.sub.2,6), 120.1 (CN), 123.5 (2C, Ar'C.sub.2,6), 124.2
(ArC.sub.6), 124.7 (ArC.sub.7), 125.9 (ArC.sub.9), 133.2
(ArC.sub.8), 135.3 (2C, Ar''C.sub.3,5), 145.4 (Ar''C.sub.1), 146.2
(Ar'C.sub.1), 153.0 (ArC.sub.10), 155.6 (Ar'C.sub.4), 157.6
(ArC.sub.2), 167.9 (ArC.sub.4).
MS (ESI) m/z 369 (M.sup.++1).
Example 3-2
Synthesis of the Diaryl Benzo Pyrimidine Derivative (Method
Two)
2-methoxyphenol and 2-chloro benzo pyrimidine derivative were mixed
together, and heated to 150.about.210.degree. C. until the
reactants melt completely, and frit reaction lasts for 1 h. When
the TLC demonstrates that the reaction was complete, the reaction
mixture was dissolved into DMF, decolored with activated carbon and
filtered, the filtration was poured into cold water; the deposited
solid was filtered out and dried. The desired compound was obtained
through recrystallization with toluene.
##STR00032##
White flocculus solid, yield: 82.9%; mp: 220.0-220.5.degree. C.;
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 3.73 (s, 3H, CH.sub.3O),
7.10 (td, 1H, J=7.6 Hz, J'=1.6 Hz, Ar'H.sub.6), 7.30 (dd, 1H, J=8.4
Hz, J'=1.2 Hz, Ar'H.sub.3), 7.35-7.41 (m, 2H, Ar'H.sub.4,5), 7.47
(td, 1H, J=8.0 Hz, J'=0.8 Hz, ArH.sub.7), 7.56 (d, 2H, J=8.8 Hz,
Ar''H.sub.2,6), 7.71 (d, 1H, J=8.4 Hz, ArH.sub.6), 7.84 (d, 2H,
J=8.8 Hz, Ar''H.sub.3,5), 7.89 (td, 1H, J=8.4 Hz, J'=1.2 Hz,
ArH.sub.8), 8.22 (d, 1H, J=8.4 Hz, ArH.sub.9), 10.06 (s, 1H,
NH).
.sup.13C NMR (DMSO-d.sub.6) .delta. (ppm) 55.8 (CH.sub.3O), 102.3
(Ar''C.sub.4), 111.6 (ArC.sub.5), 113.4 (Ar'C.sub.3), 118.3 (2C,
Ar''C.sub.2,6), 119.5 (CN), 121.0 (ArC.sub.6), 123.1 (Ar'C.sub.5),
123.8 (ArC.sub.7), 124.2 (Ar'C.sub.6), 125.4 (ArC.sub.9), 127.2
(Ar'C.sub.4), 132.6 (2C, Ar''C.sub.3,5), 134.9 (ArC.sub.8), 140.9
(Ar''C.sub.1), 144.9 (Ar'C.sub.1), 151.1 (ArC.sub.10), 152.6
(Ar'C.sub.2), 155.2 (ArC.sub.2), 166.8 (ArC.sub.4).
MS (ESI) m/z 367 (M.sup.+-1).
##STR00033##
The operation was the same as above mentioned. White powder, yield:
89.6%; mp: 230.7-231.9.degree. C.; .sup.1H NMR (DMSO-d.sub.6)
.delta. (ppm) 7.38-7.43 (m, 3H, Ar''H.sub.2,6+Ar'H.sub.4), 7.48 (t,
1H, J=7.6 Hz, ArH.sub.7), 7.55-7.59 (m, 4H,
Ar'H.sub.3,5+Ar'H.sub.2,6), 7.72 (d, 1H, J=8.0 Hz, ArH.sub.6),
7.87-7.91 (m, 3H, Ar''H.sub.3,5+ArH.sub.8), 8.23 (d, 1H, J=8.0 Hz,
ArH.sub.9), 10.04 (s, 1H, NH).
.sup.13C NMR (DMSO-d.sub.6) .delta. (ppm) 102.3 (Ar''C.sub.4),
112.0 (ArC.sub.5), 118.5 (2C, Ar''C.sub.2,6), 119.5 (CN), 122.2
(2C, Ar'C.sub.2,6), 123.7 (ArC.sub.6), 124.2 (ArC.sub.7), 125.4
(Ar'C.sub.4), 126.0 (ArC.sub.9), 129.9 (2C, Ar'C.sub.3,5), 132.6
(2C, Ar''C.sub.3,5), 134.9 (ArC.sub.8), 144.8 (Ar''C.sub.1), 152.4
(ArC.sub.10), 152.6 (Ar'C.sub.1), 155.1 (ArC.sub.2), 167.2
(ArC.sub.4).
MS (ESI) m/z 337 (M.sup.+-1).
##STR00034##
The operation was the same as above mentioned. White flocculus
solid, yield: 86.6%; mp: 220.6-220.8.degree. C.; .sup.1H NMR
(DMSO-d.sub.6) .delta. (ppm) 2.39 (s, 3H, CH.sub.3), 7.26 (d, 2H,
J=8.8 Hz, Ar''H.sub.2,6), 7.33 (d, 2H, J=8.4 Hz, Ar'H.sub.3,5),
7.46 (t, 1H, J=8.0 Hz, ArH.sub.7), 7.58 (d, 2H, J=8.4 Hz,
Ar'H.sub.2,6), 7.70 (d, 1H, J=8.4 Hz, ArH.sub.6), 7.87 (td, 1H,
J=8.0 Hz, J'=1.6 Hz, ArH.sub.8), 7.94 (d, 2H, J=8.8 Hz,
Ar''H.sub.3,5), 8.20 (dd, 1H, J=8.4 Hz, J'=0.8 Hz, ArH.sub.9), 9.98
(s, 1H, NH).
.sup.13C NMR (DMSO-d.sub.6) .delta. (ppm) 20.5 (CH.sub.3), 102.4
(Ar''C.sub.4), 112.1 (ArC.sub.5), 118.5 (2C, Ar''C.sub.2,6), 119.5
(CN), 121.8 (2C, Ar'C.sub.2,6), 123.7 (ArC.sub.6), 124.2
(ArC.sub.7), 125.4 (ArC9), 130.2 (2C, Ar'C.sub.3,5), 132.6 (2C,
Ar''C.sub.3,5), 134.8 (ArC.sub.8), 135.1 (Ar'C.sub.4), 144.9
(Ar''C.sub.1), 150.1 (ArC.sub.10), 152.5 (Ar'C.sub.1), 155.1
(ArC.sub.2), 167.2 (ArC.sub.4).
MS (ESI) m/z 351 (M.sup.+-1).
##STR00035##
The operation was the same as above mentioned. Yellow acicular
solid, yield: 79.4%; mp: 218.6-220.2.degree. C.; .sup.1HNMR
(DMSO-d.sub.6) .delta. (ppm) 2.20 (s, 3H, CH.sub.3), 7.51 (t, 1H,
J=7.6 Hz, ArH.sub.7), 7.61 (d, 2H, J=8.8 Hz, Ar''H.sub.2,6),
7.73-7,76 (m, 2H, Ar'H.sub.5+ArH.sub.6), 7.88-7.94 (m, 4H,
ArH.sub.8+Ar'H.sub.5+Ar''H.sub.3,5), 8.27 (d, 1H, J=8.0 Hz,
ArH.sub.9), 10.09 (s, 1H, NH).
.sup.13C NMR (DMSO-d.sub.6) .delta. (ppm) 16.3 (CH.sub.3), 102.6
(Ar''C.sub.4), 111.2 (ArC.sub.5), 117.6 (Ar'C4), 118.5 (2C,
Ar''C.sub.2,6), 118.9 (CN), 119.5 (ArC.sub.6), 123.6 (Ar'C.sub.2),
124.5 (ArC.sub.7), 125.6 (ArC.sub.9), 132.7 (ArC.sub.8), 132.8 (2C,
Ar''C.sub.3,5), 133.3 (Ar'C.sub.3), 135.3 (Ar'C.sub.5), 135.5
(Ar'C.sub.6), 144.7 (Ar''C.sub.1), 147.6 (ArC.sub.10), 152.8
(Ar'C.sub.1), 154.9 (ArC2), 165.2 (ArC.sub.4).
MS (ESI) m/z 511 (M.sup.++1).
Effect Example 1
Anti HIV Biological Activity Test
NVP, DLV and EFV were used as control substances, the inhibitory
activities of part of the target compounds are shown in Table
1.
##STR00036##
TABLE-US-00001 TABLE 1 Anti-HIV activities and cell toxicities of
Compounds 1-32 on MT-4 cells EC50 HIV-1(IIIB) 103N + 181C CC.sub.50
Compounds R1 R2 R4 (nM) (.mu.M) (.mu.M) SI.sup.b 1 H H 2.9 38.84
38.84 13393 2 Cl H 19.5 20.11 20.10 1031 3 NHCH3 H 8.9 54.20 54.19
6089 4 OCH3 H 12.8 42.23 42.23 3299 5 H Me 5.8 19.91 19.91 3432 6
Cl Me 25.7 44.72 44.72 1740 7 NHCH3 Me 15.8 36.53 36.53 2312 8 OCH3
Me 17.8 31.82 31.81 1787 9 Cl i-Pr 6-CN 50.0 3.36 435.55 8711 10 H
H 1-Me 3.46 11.00 114.11 32981 11 H H 3-Me 2.3 >70.94 71.16
30941 12 H H 1,3-diMe 4.1 1.17 313.39 76436 13 H H 1,6-diBr 4.6
>50.39 51.06 11099 14 H H 6-CN 3.3 6.30 67.81 20548 15 H H
1-Br-6-CN 1.6 0.24 290.00 181247 16 H H 3-Br-6-CN 1.1 >56.53
55.39 50357 17 NHCH3 Me 1-Br 15.4 6.15 177.01 11494 18 NHCH3 Et
1-Br-6-CN 6.2 >59.52 303.92 49020 19 NHCH3 i-Pr 6-CN 7.6 4.58
265.00 34868 NVP 75.1 -- 5.41 >72 DLV 72 -- 0.86 12 EFV 3 560
4.30 >1434 .sup.aIC.sub.50: the concentration of an inhibitor
that is required for 50% inhibition of HIV-1 RT; .sup.bSI:
Selectivity index, the ratio of CC.sub.50/IC.sub.50.
The results show that the compounds included by the general
chemical formula possess strong anti HIV-1 virus activity, slight
cell toxicity and high selectivity index; and a part of the
compounds also exhibit certain anti HIV-2 action, this is different
from the classical NNRTIs.
Effect Example 2
Anti HIV-1 Biological Activity Test
Screening for in vitro activity of anti HIV-1 reverse transcriptase
(HIV-1 RT) (tested by The National Center for Drug Screening), the
materials and methods were as following: 1. HIV-1 RT: Extracted in
the lab and stored. 2. Sample treatment: sample was dissolved in
DMSO to achieve suitable concentration before use, and 10-fold
diluted with double distilled water, 8 dilution degrees per sample
(sample was not dissolved completely in double distilled water). 3.
Positive control medicine: nevirapine (NVP), Nanjing Zezhong
Medical & Chemical Information Research Center. 4. Test method:
after dilution, the sample was added to the reaction buffer
containing Biotin-dUTP and genetically engineered target enzyme to
incubate under optimal reaction conditions, avidin labeled
horseradish peroxidase system was used as colour reagent, and the
value of OD450 was determined.
The inhibitory activities of parts of target compounds are shown in
Table 2.
##STR00037##
TABLE-US-00002 TABLE 2 Biological activities of the compounds to
wild type, mutant type HIV-1 and HIV-1 RT EC50.sup.b WT(IIIB) 103N
+ 181C CC.sub.50 Compounds R13 R14 X IC.sub.50.sup.a (ug/ml) (nM)
(nM) (.mu.M) SI.sup.d 20 OMe H O 0.9 1.2 380 160.84 .gtoreq.134032
21 H OMe O 0.52 0.9 318070 142.41 >158228 22 OMe OMe O 0.04 0.8
160 20.00 .gtoreq.25000 23 Cl H O -- 1.8 700 86.34 47964 24 Cl OMe
O -- 0.6 150 15.42 .gtoreq.25701 NVP 0.37 75.1 -- 5.41 >72 DLV
72 -- 0.86 12 EFV 3 560 4.30 >1434 .sup.aIC.sub.50: the
concentration of an inhibitor that is required for 50% inhibition
of HIV-1 RT; .sup.bEC.sub.50: half effect concentration, drug
concentration that is required for half of individuals to produce a
specific effect; .sup.cCC.sub.50: drug concentration required to
reduce cell viability by 50%, i.e. drug concentration that is
required for 50% cell death; .sup.dSI: Selectivity index, the ratio
of CC.sub.50/IC.sub.50.
The results show that, the compounds included by the general
chemical formula are non-nucleoside reverse transcriptase
inhibitors, and possess strong anti-HIV-1 virus activity, and
slight cell toxicity and high selectivity index; and most of the
compounds showed good inhibition ability against drug-resistant
viral strain of L103N+Y181C.
Effect Example 3
Anti-HIV Biological Activity Test
HEPT and DDI were used as control substances, the inhibitory
activities of a part of the target compounds are shown in Table
3.
##STR00038##
TABLE-US-00003 TABLE 3 Anti-HIV activities and cell toxicities of
compounds 25-54 on MT-4 cells EC50 (nM).sup.a Compounds R.sup.10
R.sup.8 Y HIV-1(IIIB) CC.sub.50 (.mu.M).sup.b SI.sup.c 25 H
2-Me--Ph O 93.7 107.6 1148 26 H 4-Br--Ph O 263 235.1 894 27 H
-3-Me--Ph O 625 >351.9 >563 28 H 4-MeO--Ph O 187 >3397.4
>1810 29 H 2-MeO--Ph O 30 >185.6 >6186 30 H Ph O 887
>364.6 >411 31 H 4-Me--Ph O 42 339.8 8091 32 H
2,4-diBr-6-Me--Ph O 17.6 156.9 8917 33 H -4-CN-2-Me--Ph O 28
>333.0 >11893 34 H 2,4,6-triBr--Ph O 23 71 3087 35 H
2,6-diBr-4-Me--Ph O 15 23.4 1563 36 H 2,4,6-triMe--Ph O 23 >34.1
>1484 37 H 2,4-diCl--Ph O 28 113.9 4068 38 H 4-F--Ph O 156 310.0
1987 39 H 2-Cl--Ph O 57 343 6018 40 H 4-Cl--Ph O 167 >395.6
>2369 41 H 4-CN-2,6-diMeO--Ph O 2.2 >93.1 >42311 42 H
2,4,6-triCl--Ph O 3.5 244.4 69833 43 H 2,6-diMe--Ph O 46 >639.5
>13902 44 H Ph S 752 494.1 657 45 H 4-CN-2,6-diMe--Ph O 3.6
>172.2 >47832 46 H 4-CN-2,6-diEtO--Ph O 2.9 >99.3
>34239 47 H 4-CN-2-EtO-6-.sup.nPrO--Ph O 3.2 >66.7 >20842
48 H 2-Cl-4-CN-6-MeO--Ph O 5.6 >173.0 >30899 49 H
2-Cl-4-CN-6-EtO--Ph O 5.9 >594.1 >10692 50 H
4-CN-2-MeO-6-.sup.iPrO--Ph O 6.7 >65.8 >9823 51 H Ph SO.sub.2
589 >215.0 >365 52 H 4-CN-2-EtO-6-MeO--Ph O 2.6 >130.3
>50129 53 H 4-CN-2-MeO-6- O 5.4 >57.7 >10691 54 Cl
2,4,6-Me--Ph O 1.8 147.0 81672 BOE/BIRG587(nevirapine) 75.1
>15.02 >252 DDN/AZT 5.17 >93.548 >18094
DMP266(efavirenz) 3 >6.336 >2174 .sup.aIC.sub.50: the
concentration of an inhibitor that is required for 50% inhibition
of HIV-1 RT; .sup.bCC.sub.50: drug concentration required to reduce
cell viability by 50%, i.e. drug concentration that is required for
50% cell death; .sup.cSI: Selectivity index, the ratio of
CC.sub.50/IC.sub.50.
The results show that, the compounds included by the general
chemical formula generally possess strong anti-HIV-1 virus
activity, and slight cell toxicity and high selectivity index.
All the documents cited herein are incorporated into the invention
as reference, as if each of them is individually incorporated.
Further, it would be appreciated that, in the above teaching of
invention, the skilled in the art could make certain changes or
modifications to the invention, and these equivalents would still
be within the scope of the invention defined by the appended claims
of the application.
* * * * *